The dioxin/aryl hydrocarbon receptor (AhR) belongs to a specific class of transcription factors, basic helix-loop-helix/Per-Arnt-Sim domain (bHLH/PAS) proteins, which is emerging as an important battery of regulatory factors seemingly designed to respond to environmental cues. Other members of this family include the hypoxia-inducible factor HIF-1α, the rhythmicity regulatory protein Clock, the neuro-regulatory protein Sim, and Arnt, an essential partner factor for all of the factors mentioned above including the AhR (1). Arnt is recruited to the AhR in a ligand-dependent manner to facilitate recognition of xenobiotic response elements of target promoters.
The ligand-activated AhR mediates transcriptional activation of a network of genes encoding enzymes such as CYP1A1, CYP1A2, glutathione S-transferase Ya, UDP-glucuronosyl-transferase 1A6 and NAD(P)H quinone oxidoreductase-1 that function in the oxidative metabolism of xenobiotics (2). Well-characterized ligands of the AhR are polycyclic aromatic hydrocarbons formed during combustion processes and polychlorinated dioxins and, coplanar biphenyls that contaminate industrial chemicals and the environment (2). Thus, AhR-mediated signalling pathways provide a first line of defence against potentially toxic environmental pollutants. On the other hand, induction of oxidative metabolic processes by the AhR can also cause the production of highly carcinogenic metabolites, creating a strong link between AhR activation and chemical carcinogenesis (3). In addition, the receptor appears to mediate by as yet unclear mechanisms a wide range of toxic effects by chlorinated dioxins including birth defects, impaired reproductive capacity, and immune suppression (1). A number of independent loss-of-function studies performed by gene disruption in mice have not yielded conclusive information with regard to a possible developmental role of the receptor (4–7). In view of its critical role in mediating metabolic responses to environmental pollutants, the sole biological function of the AhR could therefore be restricted to regulation of adaptive responses to xenobiotics. This notion seems to be corroborated by the fact that a putative physiological function of the AhR remains to be determined. Against this background the present inventors have performed a gain-of-function study to examine possible biological functions of the AhR system. To this end, a constitutively active AhR mutant (CA-AhR) was created and expressed in transgenic nice to study possible AhR-mediated biological effects that are generated in the absence of any exposure to environmental contaminants.